Irritable Bowel Syndrome (IBS) is the most common functional gastrointestinal disorder, leading to significant impact on both patients and society. The cardinal IBS symptoms of pain, discomfort and altered bowel habits likely arise from a combination of stress modulated alterations in autonomic nervous system (ANS) regulation of the gut and altered perception of visceral stimuli. The role of central stress networks in this process has been supported by neuroimaging data. This Mentored Career Development Proposal is designed to provide the candidate with skills to integrate the rapidly emerging techniques of neuroimaging, ANS analysis, and clinical skills in gastroenterology to perform cutting edge translational research in functional gastrointestinal disorders. Acquisition of these skills will occur during work on a series of hypothesis driven clinical projects with experts in the field, and with didactic training. Phase I of the proposal involves analysis of fMRI, PET, and ANS data collected during aversive visceral stimulation to examine the hypothesis that there is an increased sympathetic/parasympatheticbalance among IBS patients, particularly males. The central networks involved in ANS responses among IBS patients compared to controls will be delineated, and sex-based differences examined. Phase II continues the candidate's development via study of ANS responses to psychological stress, with the hypothesis that IBS patients will have greater ANS activation. First, changes in sigmoid tone during an experimental stressor will be tested as gut-specific ANS surrogate measure and correlated with skin conductance and heart rate variability. Second, imaging with fMRI will be used to determine the central ANS circuitry involved in emotional responses using the analytic tools of functional and effective connectivity. ANS reflexes in IBS patients will be tested via time course analysis for central and peripheral responses to the Valsalva maneuver during high resolution fMRI to assess for generalized ANS dysfunction. Evaluation of sex differences in ANS reponse will be emphasized, given the striking female predominance in this and many other functional disorders. Relevance: Irritable Bowel Syndrome affects up to 15% of the United States population, making it an important public health issue. The proposed training will provide the candidate with a novel set of skills to use in investigating the potential causes of IBS, and developing new treatment strategies.